The long-term goal of this work is to develop novel drugs for the treatment of metabolic syndrome (MetS). MetS is an assemblage of associated clinical disorders recognized only some 20 years ago to be linked. They include insulin resistance, hypertension, dyslipidemia (i.e. hypertriglyceridemia and low HDL levels), glucose intolerance, and obesity. The incidence of MetS has reached epidemic proportions afflicting ~64 million Americans and significantly increasing the risk of coronary heart disease (CHD), atherosclerosis, diabetes, myocardial infarction, stroke and even death in those afflicted. At this time there are no drugs available for the treatment of MetS per se. Although drugs do exist for the individual components, complications due to drug interactions, side effects, and the sheer number of drugs that are needed, along with the serious consequences of the disease, make the development of a new approach urgent. To address this need, we will adopt a novel approach to the problem, designing antagonists that target the nuclear receptor HNF4a. HNF4a is a transcription factor involved in lipid and glucose homeostasis and the transcriptional regulation of genes involved in energy metabolism, as well as blood pressure homeostasis. Thus, it is involved in regulation of all components of MetS, and a growing body of biological data supports its role in the treatment of the multiple components of MetS. Current drugs that target antagonizing nuclear receptors bind to the ligand-binding site (LBS) where they alter the dynamics and structure of the receptor, resulting in an inability of necessary coactivators to bind to the coactivator-binding site (AF-2) thus interfering with transcription. Rather than focusing solely on the LBS, we will exploit the unusual multiplicity of sites in a single drug target (AF-2 and LBS) to carry out a, two-site, drug discovery strategy that leverages both experimental and theoretical efforts and provides new mechanistic approaches to overcoming MetS. To this end we will integrate in silico induced-fit docking with cell based transcription assays, X-ray crystallography, and molecular dynamics free energy pertubation and replica exchange simulations to find confirmed hits (X-ray and assays) and determine structural design criteria for lead optimization of compounds at these sites. PUBLIC HEALTH RELEVANCE: Metabolic syndrome (MetS) is an assemblage of associated clinical disorders that includes insulin resistance, hypertension, dyslipidemia (i.e. hypertriglyceridemia and low HDL levels), glucose intolerance, and obesity. The incidence of MetS has reached epidemic proportions afflicting ~64 million Americans and significantly increasing the risk of coronary heart disease, atherosclerosis, diabetes, myocardial infarction, stroke and even death in those afflicted. To develop a drug to address this complex disease, we will take a novel approach, designing compounds that target the nuclear receptor HNF4a, which is involved in regulating all components of this syndrome.